1. Field of the Invention
This invention relates to methods of promoting weight gain.
2. Description of the Related Art
Weight loss after head injury is a common side effect (Pepe et al. (1999), The metabolic response to acute traumatic brain injury and implications for nutritional support, Journal of Head Trauma and Rehabilitation, 5: 462-474; Borzotta et al. (1994), Enteral versus parenteral nutrition after severe closed head injury, Journal of Trauma, 37(3): 459-468; Flakoll et al. (1995), Protein and glucose metabolism during isolated closed-head injury, American Journal of Physiology, 269(4Pt1): E636-E641). There are also no treatments currently available to prevent the cell death that occurs in the brain as a consequence of head injury.
Similarly, weight loss is a common symptom associated with chronic neurological diseases, such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease and multiple sclerosis. Treatments available at present for such chronic neurological diseases only target symptoms. No drugs are currently available to intervene in the disease process.
Various growth factors have been shown to be neuroprotective and therefore have utility in the prevention or inhibition of neural cell death (AU 700838; WO 95/17204; U.S. Pat. Nos. 5,714,460; 5861373; EP 625050; WO 99/15912; WO 00/13650). However, it has been shown in human patients that growth factors can cause weight loss. Nerve growth factor (NGF) administered intracerebroventricularly to patients with Alzheimer""s disease can cause marked weight reduction (Eriksdotter et al. (1998), Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer""s disease, Dementia and Geriatric Cognitive Disorders, 9(5): 246-257).
Weight loss following administration of growth factors to the brain has also been found to occur in monkeys (Miyoshi et al. (1997), Glial cell line-derived neurotrophic factor-Levodopa interactions and reduction of side effects in Parkinsonian monkeys, Annals of Neurology, 42: 208-214). Similarly, the following growth factors have been shown to either decrease normal body weight gain or cause weight loss when infused in the brain of adult rats following either partial or full lesions to an area of the brain, such as a partial fimbria-fornix transection: brain-derived neurotrophic factor (BDNF) (Lapchak et al. (1992), BDNF and NGF treatment in lesioned rats: effects on cholinergic function and weight gain, NeuroReport, 3: 405-408; Altar et al. (1994), Efficacy of brain-derived neurotrophic factor and neurotrophin-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions, Journal of Neurochemistry, 63: 1021-1032), basic fibroblast growth factor (bFGF) (Araujo et al. (1993), Effects of chronic basic fibroblast growth factor administration to rats with partial fimbrial transections on presynaptic cholinergic parameters and muscarinic receptors in the hippocampus: comparison with nerve growth factor, Journal of Neurochemistry, 61: 889-910; Williams et al. (1996), Glial cell line-derived neurotrophic factor sustains axotomized basal forebrain cholinergic neurons in vivo: dose response comparison to nerve growth factor and brain-derived neurotrophic factor, Journal of Pharmacology and Experimental Therapeutics, 277: 1140-1151), glial-derived neurotrophic factor (GDNF) (Giehl et al. (1998), Infusion of GDNF into the cerebral spinal fluid through two different routes: effects on body weight and corticospinal neuron survival, NeuroReport, 9: 2809-2813; Williams et al. (1996), Glial cell line-derived neurotrophic factor sustains axotomized basal forebrain cholinergic neurons in vivo: dose response comparison to nerve growth factor and brain-derived neurotrophic factor, Journal of Pharmacology and Experimental Therapeutics, 277: 1140-1151) and nerve growth factor (NGF) (Winkler et al. (1995), Effects of nerve growth factor treatment on rats with lesions of the nucleus basalis magnocellularis produced by ibotenic acid, quisqualic acid, and AMPA, Experimental Neurology, 136: 234-250).
Furthermore, BDNF, GDNF and NGF administered to the brain of normal, unlesioned rats have been shown to cause weight loss (Pelleymounter et al. (1995), Characteristics of BDNF-induced weight loss, Experimental Neurology, 131: 229-238; Martin et al. (1996), Intranigral or intrastriatal injections of GDNF: effects on monoamine levels and behavior in animals, European Journal of Pharmacology, 317: 247-256; Williams (1991), Hypophagia is induced by intracerebroventricular administration of nerve growth factor, Experimental Neurology, 113: 31-37).
In contrast, insulin-like growth factor I (IGF-I) has been shown to cause weight gain in humans when administered intravenously after moderate to severe head injury (Hatton et al. (1997), Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: a phase II safety and efficacy trial, Journal of Neurosurgery, 86(5): 779-786). Similarly, IGF-I has been shown to cause weight gain when administered into the brain following a transient ischemia to the forebrain in adult rats (Zhu et al. (1994), Intraventricular administration of insulin and IGF-1 in transient forebrain ischemia, Journal of Cerebral Blood Flow and Metabolism, 14(2): 237-242).
GPE is the tripeptide glycyl-L-prolyl-L-glutamic acid (gly-pro-glu). GPE and its dipeptide analogs GP (glycl-L-proline, gly-pro) and PE (L-prolyl-L-glutarnic acid, pro-glu) were first disclosed in EP 366638. The suggestion has been made in EP 366638 that GPE has neuromodulatory properties. GPE has also been established as having neuroprotective properties and therefore has utility in the prevention or inhibition of neuronal and glial cell death (WO 95/17204, AU 700838). GPE has also been established as having neuromodulatory properties and therefore has utility in increasing the effective amount of choline acetyltransferase (ChAT), nitric oxide synthase (NOS), glutamic acid decarboxylase (GAD) (WO 98/14202) and tyrosine hydroxylase (WO 99/65509) in the brain.
This invention is a method of promoting weight gain in a mammal, especially a human, having a condition that leads to decreased weight gain or weight loss, comprising increasing the effective concentration of a GPE-related compound in the central nervous system of the mammal. This increase may be achieved by administration to the mammal of an effective amount of a GPE-related compound, a prodrug thereof, or an implant containing cells that express the GPE-related compound or prodrug.
In another aspect, this invention is the use of a GPE-related compound, a prodrug thereof, or an implant containing cells that express the GPE-related compound or prodrug in the manufacture of a medicament for promoting weight gain in a mammal having a condition that leads to decreased weight gain or weight loss; and the medicament so made.